The broad objective of this project is to determine the mechanism of morphine-induced immunosuppression and to further characterize the combined effects of morphine and stress on the immune system. Specifically, the experiments described in this proposal will test the hypotheses that the inhibition of immune cell activities by morphine: 1)is mediated through the activation of centrally-located opioid receptors 2)requires the stimulation of the autonomic nervous system 3)results in an increased sensitization of the immune system to stress- induced immunosuppression The Specific Aims which will examine these hypotheses will be: Aim #1: To identify the central site(s) which are involved in the peripheral immunosuppressive effects of morphine. These studies will determine the localization of single or multiple sites within the central nervous system through which the effects of morphine on the immune system are mediated. Initially areas of the brain which have been shown to be rich in opioid receptors will be examined. Aim #2: To pharmacologically characterize the subtype of opioid receptors involved in the immunosuppressive effects of morphine. Once the central sites involved in morphine-induced immunosuppression have been localized, opioid receptor specificity at these sites will be examined. Aim #3: To determine whether the immunosuppressive effects of morphine mediated through the activation of the autonomic nervous system. Our previous studies have shown that the immunosuppressive effects of morphine are independent of the stimulation of the hypothalamic-pituitary-adrenal axis. Therefore, these studies will examine whether morphine-induced suppression of lymphocyte proliferation requires the participation of the peripheral sympathetic and/or parasympathetic nervous systems. Aim #4: To continue the evaluate whether the inhibition by morphine of blood lymphocyte proliferation represents changes in other parameters of cellular and humoral immunity. These studies will continue to evaluate the effects of morphine on leukocyte phenotypic expression, interleukin secretion and receptor expression. Additional studies will assess the immune consequences of multiple or continuous exposures to morphine on the delayed type hypersensitivity reaction, cytolytic T lymphocyte activity, and T-cell dependent and independent antibody responses. Aim #5: To examine mechanisms contributing to the increased sensitivity of morphine-tolerant rats to the immunosuppressive effects of stress. In these studies we will continue to evaluate whether exposures of morphine- tolerant animals to different stressors results in an increased susceptibility to immunosuppression. In addition we will determine whether changes have occurred in morphine-tolerant animals which may contribute to a greater 'immune sensitivity' upon the exposure to a stressor. In this regard, changes in the sensitivity of immune cells and/or the neuroendocrine response to stress in morphine-tolerant animals will be determined. Finally, experiments will also investigate whether the increased susceptibility of morphine-tolerant animals involves alterations in the central levels of cholecystokinin (CCK), a putative antiopioid peptide.